Liu Kuisheng, Sun Yuanyuan, Liu Dahai, Ye Shoudong
Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, PR China.
Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei 230601, PR China.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):616-622. doi: 10.1016/j.bbrc.2017.06.086. Epub 2017 Jun 16.
Inhibition of Wnt/β-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self-renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/β-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (Foxd3) was most abundant. Forced expression of Foxd3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of Foxd3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. Foxd3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/β-catenin signaling inhibitor. These findings highlight an important role for Foxd3 in regulating EpiSCs and will expand current understanding of the primed pluripotency.
抑制Wnt/β-连环蛋白信号通路有助于小鼠上胚层干细胞（EpiSCs）的获得，并且能显著促进EpiSC的自我更新。然而，具体机制仍不清楚。在此，我们发现IWR1（一种Wnt/β-连环蛋白信号通路抑制剂）与ROCK抑制剂Y27632联合使用时，能使EpiSCs在血清培养基中实现长期自我更新。通过转录组数据分析，我们获得了一组由IWR1诱导的候选转录因子。其中，叉头框D3（Foxd3）最为丰富。在EpiSCs中，强制表达Foxd3能够重现IWR1促进自我更新的作用。相反，敲低Foxd3会严重损害对IWR1的反应能力，导致多能性标志物消失并出现分化表型。因此，Foxd3对于介导Wnt/β-连环蛋白信号通路抑制剂下游的自我更新是必要且充分的。这些发现凸显了Foxd3在调控EpiSCs中的重要作用，并将拓展我们目前对始发态多能性的理解。
